New treatment guidelines on Cushing's disease

It is important to treat patients with Cushing's disease as rapidly as possible to limit its long-term mortality and morbidity. Selective transphenoidal pituitary adenomectomy remains the treatment of choice but, unfortunately, the rate of cure at long-term follow-up is suboptimal and recurrences are high, even in the hands of expert neurosurgeons. Treatment options for persistent or relapsed disease include repeat trasphenoidal pituitary surgery, radiotherapy or bilateral adrenalectomy. Medical treatment, a second-line treatment option, may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. Cabergoline and pasireotide (SOM230), two pituitary tumor-directed drugs, are the most exciting news in the human pharmacological approach. However, the use of these drugs in clinical practice and their real impact in the management of patients is yet to be determined. The treatment of patients with Cushing's disease is complex and requires a multidisciplinary and individualized approach to patient management using cost-benefit analyses

Analysis of geospatial behaviour of visitors of urban gardens: is positioning via smartphones a valid solution?

Tracking locations is practical and speditive with smartphones, as they are omnipresent devices, relatively cheap, and have the necessary sensors for positioning and networking integrated in the same box. Nowadays recent models have GNSS antennas capable of receiving multiple constellations. In the proposed work we test the hypothesis that GNSS positions directly recorded by smartphones can be a valid solution for spatial analysis of people's behaviour in an urban garden. Particular behaviours can be linked to therapeutic spots that promote health and well-being of visitors. Three parts are reported: (i) assessment of the accuracy of the positions relative to a reference track, (ii) implementation of a framework for automating transmission and processing of the location information, (iii) analysis of preferred spots via spatial analytics. Different devices were used to survey at different times and with different methods, i.e. in the pocket of the owner or on a rigid frame. Accuracy was estimated using distance of each located point to the reference track, and precision was estimated with static multiple measures. A chat-bot through the Telegram application was implemented to allow users to send their data to a centralized computing environment thus automating the spatial analysis. Results report a horizontal accuracy below ~2.3 m at 95% confidence level, without significant difference between surveys, and very little differences between devices. GNSS-only and assisted navigation with telephone cells also did not show significant difference. Autocorrelation of the residuals over time and space showed strong consistency of the residuals, thus proving a valid solution for spatial analysis of walking behaviour

Inflammation as a Link between Obesity and Metabolic Syndrome

The metabolic syndrome is a complex of clinical features leading to an increased risk for cardiovascular disease and type 2 diabetes mellitus in both sexes. Visceral obesity and insulin resistance are considered the main features determining the negative cardiovascular profile in metabolic syndrome. The aim of this paper is to highlight the central role of obesity in the development of a chronic low-grade inflammatory state that leads to insulin resistance, endothelial and microvascular dysfunctions. It is thought that the starting signal of this inflammation is overfeeding and the pathway origins in all the metabolic cells; the subsequent increase in cytokine production recruits immune cells in the extracellular environment inducing an overall systemic inflammation. This paper focuses on the molecular and cellular inflammatory mechanisms studied until now

Does major depressive disorder cause osteoporosis in a young man?

We recently reviewed the literature about major depressive disorder (MDD) as an additional risk factor for osteoporosis (1, 2). Most of the studies examining the association between depression and osteoporosis have been conducted in women whereas the few existing studies on depression and osteoporosis conducted in men have been limited to the elderly (3, 4). An association between depression and lower BMD has been reported in elderly Asian men (4), however, the same association was not observed in community-dwelling, elderly Caucasian men (3). Very little is known about osteoporosis in young men (5, 6). Results from the Third National Health and Nutrition Examination Survey (NHANES III) show that major depressive episode (MDE) is associated with 2% lower BMD at the total proximal femoral level in multivariate models in young men but not in women (5). The existence of a relationship between depression and osteoporosis in young men remains controversial

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial

International audiencePurpose Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study. Methods 162 patients entered the core study. 58 patients who had mean UFC B ULN at month 12 or were bene-fiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300–1,200 lg bid). Dose titration was permitted according to efficacy or drug-related adverse events. Results 40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0 % (29/58) and 34.5 % (20/58) had controlled UFC (UFC B ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3 % (95 % CI 40.7–73.9; n = 52) and 62.1 % (50.8–73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received C1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6 %), nausea (48.1 %), hyperglycemia (38.9 %), and cholelithi-asis (31.5 %). No new safety issues were identified during the extension. Conclusions Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease.-1) contains supplementary material, which is available to authorized users